Recommends

Comments

We recently witnessed the discovery of many Aβ receptors, but the exact signaling pathway through which Aβ (oligomers) mediated synaptic dysfunction (inhibition of LTP) is still not identified. This paper elegantly demonstrates the involvement of a signaling pathway that involves caspases, Akt1, and GSK-3β.

Taking last year’s discovery on the involvement of caspases and LTD from Morgan Sheng’s lab (Li et al., 2010), the authors explored whether caspases could be involved in Aβ-induced LTP deficits. Indeed, Aβ induced LTP inhibition-required caspase-3 and/or caspase-7. These findings tie in nicely with the recent report that showed caspase-3 triggers early synaptic alterations in an AD mouse model (D’Amelio et al., 2011). Since Li et al. previously showed that caspase-mediated Akt1 cleavage is required for LTD, in the current study the authors studied whether caspase-3-mediated Akt1 cleavage was required for Aβ inhibition of LTP. By using mutants of Akt1 that are resistant to caspase cleavage, the authors quite nicely demonstrated that this is so. Following this line, the authors then investigated whether Akt inhibition-induced activation of GSK-3β is essential for this LTP inhibition, and sure enough, they find this to be the case as well.

Overall, this study shows that the caspase-3/7-Akt inhibition-GSK-3β activation pathway is critically important for Aβ inhibition of LTP. There are many reasons why this study is quite important:

1. It elucidates the signaling axis and hence also identifies therapeutic targets for AD: If Aβ has other physiological functions, then instead of inhibiting Aβ production, one could specifically target LTP effects by targeting one of these signaling players.

2. This study again highlights a novel role of caspases outside their “apoptosis” role.

3. Akt1 and GSK-3β, two kinases that have been previously implicated in tau phosphorylation, now are identified as key signaling proteins for LTP inhibition! In a recent RNAi-based screen for Aβ production, we identified both Akt1 and Akt2 as players involved in APP processing (Bali et al., 2011, under revision).

All of these data suggest that the way Aβ elicits neurodegeneration might not be as linear and unidirectional as proposed by the amyloid cascade hypothesis. These results show that there are feedback loops and that particular kinases (such as Akt1) can participate in the production of Aβ, tau phosphorylation, and in synaptic dysfunction, introducing complexity in the amyloid cascade. I find this absolutely fascinating! What this tells us is that we have to view Alzheimer’s disease as a complex system and study its complexity.

This study nicely examines potential signaling activated by β amyloid that could perturb LTP. The signaling identified can play multiple roles, so their exact participation in the effects of β amyloid needs to be elucidated. As targets for Alzheimer's disease, therapy is complicated by the fact that these signaling molecules participate in important physiological processes.